Methylmercury (MeHg) is a widespread and persistent environmental factor that adversely affects the developing brain, which is far more sensitive than the adult organ. From previous poisonings, we know that exposure of the developing fetus in the mother to MeHg can cause severe consequences, from mental retardation to seizures and malformations, many times without harming the mother. However, there are concerns that more subtle exposures may harm the developing brain, altering learning and memory, for which the hippocampus is critical. In previous work, we found that exposing postnatal rats to moderate levels of MeHg rapidly impaired production of neurons and later produced deficiencies in hippocampal structure and function. We have now discovered that hippocampal neural stem cells, that produce neurons and glia, are exquisitely sensitive to MeHg, which causes them to die within hours. We now plan to define the lowest levels of MeHg that can cause stem cell death, and define its relationship to later loss of neurons and memory functions. In Aim 1 we will define how little MeHg in newborn rats can cause stem cell death, and identify which of several stem cell types are affected. Subsequently, 2 weeks later, we will count total number and types of neurons and glia to see whether killing precursors leads to later losses of specific populations of hippocampal cells, as we see with higher exposures. In Aim 2, we will determine whether lower exposures and losses of cells can impact learning and memory of the animals at 4 weeks of age. When complete, these studies will identify a new, highly sensitive target of MeHg, hippocampal stem cells, and will establish a novel model system. By focusing on the stem cells, rather than simply the whole brain organ as is frequently done, we may detect toxic effects of environmental factors that are otherwise missed. Or we may find that levels of known factors, like MeHg, thought to be safe, may actually have previously unrecognized harmful effects. This model system offers the possibility of defining the temporal sequence of molecular and cellular events that lead to subtle structural and functional changes in the brain during a critical window of developmental vulnerability. This information may shed light on the ways environmental exposures can impair learning and memory. PUBLIC HEALTH RELEVANCE: These studies will identify a new and highly sensitive target injured by environmental factors, the hippocampal stem cells, involved in learning and memory. In turn, the new cell-based strategy we have developed may be used to examine the effects of a variety of other factors currently considered safe.